Drug toxicity is a pertinent and long-standing concern of modern medicine (Nasr et al., (2011) Adv. Ther. 28: 842-856). In the United States alone, an estimated 750,000 emergency department visits per year are due to unintentional drug toxicity from both prescription and over-the-counter medicines, with more than two-thirds occurring after therapeutic drug use (Budnitz et al., (2006) JAMA 296: 1858-1866). Of the organ systems affected, the liver was most frequently implicated with a 60-80% mortality rate in the absence of liver transplant (Sakatis et al., (2012) Chem. Res. Toxicol. 25: 2067-2082; Srivastava et al., (2010) Handbook Exp. Pharmacol. pp 165-194). In addition to its effects on the end-user, drug-induced hepatotoxicity bears broad and direct implications for the productive innovation of pharmacotherapeutics.
The rising costs of clinical trials, estimated at $1.9 billion for 2013 (Willmann et al., (2008) Nat. Rev. Drug Discov. 7: 591-607), in conjunction with 90% attrition rates (Willmann et al., (2008) Nat. Rev. Drug Discov. 7: 591-607; Rudin, M. (2009) Curr. Opin. Chem. Biol. 13: 360-371; Tengowski & Kotyk (2005) Prog. Drug. Res. 62: 257-278; Wang & Yan (2008) Lab Anim. 42: 433-441) makes drug development an ever more risky endeavour (Kola & Landis (2004) Nat. Rev. Drug Discov. 3: 711-715). Even after approval is granted, the pharmaceutical industry is faced with an increasing number of drug withdrawals from the market (Sakatis et al., (2012) Chem. Res. Toxicol. 25: 2067-2082; Kola & Landis (2004) Nat. Rev. Drug Discov. 3: 711-715).
Two decades ago 40% of drug candidate attrition was due to poor pharmacokinetics and bioavailability. However, the implementation of high sensitivity liquid chromatography-mass spectrometry assays in pre-clinical evaluation saw this cause of attrition drop to below 10% by 2000 (Kola & Landis (2004) Nat. Rev. Drug Discov. 3: 711-715; Kramer et al., (2007) Nat. Rev. Drug Discov. 6: 636-649). Thus, the adoption of novel methodologies by the pharmaceutical industry as early as possible in the drug development process has historically remediated attrition rates and improved drug development outcomes (Kola & Landis (2004) Nat. Rev. Drug Discov. 3: 711-715). To this end, since drug-induced hepatotoxicity is the single most important cause of both FDA non-approval and withdrawal from the market after approval, a reduction in the cost and risk of drug development may be possible through innovative pre-clinical hepatotoxicity screening methods (Sakatis et al., (2012) Chem. Res. Toxicol. 25: 2067-2082; Tengowski & Kotyk (2005) Prog. Drug. Res. 62: 257-278; Wang & Yan (2008) Lab Anim. 42: 433-441; Kola & Landis (2004) Nat. Rev. Drug Discov. 3: 711-715; Dimasi, J. A. (2001) Clin. Pharmacol. Ther. 69: 297-307; Reese et al. (2011) Chem. Biol. Interact. 192: 60-64). Importantly, new robust methods for the pre-clinical interrogation of drug hepatotoxicity can also have added benefits of improving end-user safety and therapeutic outcomes (Kola & Landis (2004) Nat. Rev. Drug Discov. 3: 711-715; Kramer et al., (2007) Nat. Rev. Drug Discov. 6: 636-649).